The long-term human immune response to pathogens results from development of immune memory. This process is vital for health, and understanding how memory is formed and evolves is essential for rational approaches to vaccine development and vaccination. In man, how memory T cells are generated or maintained during the adult years, and how the number and type of T cell changes with re-exposure to pathogen are still poorly understood. Furthermore, how populations of humans respond to the same pathogen and to pathogen re-exposure has not been investigated at a basic level. In the Center Grant we investigate the memory response of cytotoxic, helper, and gamma/delta T cells to influenza. This pathogen is involved in recurring epidemics. It is derived from a large avian pool of viruses that by recombination in pigs can move from birds to man. Thus, the virus could be manipulated to select for more pathogenic types. In this Center Grant we will investigate the hypothesis that most T cell memory is derived from a robust network of T cells that was generated when the thymus was generating a large number of naive T cells. Using influenza as our model pathogen, we will investigate how memory T cells that are studied from blood relate to memory cells in the lung. By analyzing memory T cell repertoires in a cohort of individuals over a number of years, and correlating the results with the risk of exposure to influenza, we should develop a detailed understanding of how the complex network of memory T cells change with time and with pathogen re-exposure. The Center Grant consists of four scientific projects that approach the above issues from the point of view of: 1) Class I HLA-restricted memory T cell responses from blood. 2) Class II HLA-restricted memory T cell responses from blood. 3) Responses of T cells from bronchial alveolar lavages in comparison with those from blood. These studies will also include analyzing the possible role of gamma/delta T cells in the response. 4) Modeling the nature of the responding repertoires and generating a molecular description of the epidemiology of influenza. These studies will be supported by a number of cores that are responsible for providing common samples, common testing and common reagents. Four technical aims are proposed for advancing repertoire analysis.